Innate Immunity plays a central role in controlling Herpes Simplex virus infection and marshalling the T- and B- cell responses of adaptive immunity. The regulation of type I interferons (IFNa/p), host cytokines and chemokines are critical effectors of innate immunity. Type I IFNs function to directly limit HSV replication and activate adaptive immunity, while inflammatory cytokines and chemokines act indirectly to recruit and activate effector cells. Inflammatory cytokines are a major contributor to the morbidity and mortality associated with HSV pathogenesis. Several classes of germ-line encoded pattern recognition receptors have been shown to sense viruses and trigger type I IFN responses and/or inflammatory cytokines. These include the Toll-Like Receptors, the RNA helicases, DNA-dependent activator of IRFs (DAI) and more recently NLRP-3 (also called Cryopyrin, NALP-3). NLRP-3 is a member of the NOD-like receptor (NLR) family which has been shown to sense endogenous danger signals released from dying cells, environmental insults and the DNA virus, adenovirus. Like other NLRs, NLRP~3 forms large multiprotein complexes in cells termed 'inflammasomes' which control the activity of pro-caspase-1. Activated caspase-1 controls the maturation of pro-IL-ip and related cytokines into their active, cleaved and released forms. Preliminary data presented in this proposal implicates NLRP-3 and/or the inflammasome in innate immunity to HSV. Firstly, HSV activates caspase-1 mediated processing of pro-ILIp. The importance of these events is highlighted by the increased sensitivity of IL1R and IL18R-deficient mice to lethal HSV challenge and by the ability of ICPO, an immediate early HSV gene to subvert inflammasome activation. Secondly, unlike other components of the inflammasome, NLRP-3 plays a detrimental role during HSV infection in vivo; NLRP-3-deficient mice are protected from lethal HSV infection. Finally, we implicate NLRP-3 in transcriptional regulation of type I IFNs and inflammatory cytokines in response to AT-rich DNA motifs identified in the HSV genome. AT-rich DNA sensing appears to involve NLRP-3, Tank binding kinase (TBK)-1 and Interferon Regulatory Factor (IRF)-I, but not other components of the inflammasome. RELEVANCE (See Instructions): A detailed understanding of how type I IFNs and inflammatory cytokines are controlled in response to HSV infection is important clinically for the development of therapeutic agents to either enhance the innate immune response to HSV or to dampen it in situations where these responses are harmful to the host, e.g., cytokine-mediated encephalitis.